A novel mutation in PLP1 causes severe hereditary spastic paraplegia type 2

• Hereditary spastic paraplegia type 2 is a severe central nervous system disorder.
• Mutations in PLP1 are associated with Hereditary Spastic Paraplegia.
• A mutation in the transmembrane domain of PLP1 causes a severe clinical phenotype.

Hereditary spastic paraplegia (HSP) type 2 is a proteolipid protein (PLP1)-related genetic disorder that is characterized by dysmyelination of the central nervous system resulting primarily in limb spasticity, cognitive impairment, nystagmus, and spastic urinary bladder of varying severity. Previously reported PLP1 mutations include duplications, point mutations, or whole gene deletions with a continuum of phenotypes ranging from severe Pelizaeus–Merzbacher disease (PMD) to uncomplicated HSP type 2. In this manuscript we report a novel PLP1 missense mutation (c.88G>C) in a family from Argentina. This mutation is in a highly conserved transmembrane domain of PLP1 and the mutant protein was found to be retained in the endoplasmic reticulum when expressed in vitro. Due to the variable expressivity that characterizes these disorders our report contributes to the knowledge of genotype–phenotype correlations of PLP1-related disorders.